The impact of CAR T-cell therapy on quality of life of patients with triple-class refractory multiple myeloma

Over the last 15 years, novel treatments have significantly improved the overall survival of patients with multiple myeloma (MM). As patients start to live longer, the question of what quality of life (QoL) they experience during this time becomes more important. Health-related QoL (HRQoL) has been recorded to decrease over time and with each relapse in patients with MM. Therefore, it is crucial to study which therapeutic agents are able to improve QoL, along with alleviating the burden of disease.

How is QoL measured in MM clinical trials?

In clinical trials, questionnaires may be chosen as the method to assess patient-reported QoL. These questionnaires examine patient’s physical, emotional, and social functioning using graded scoring. The following different questionnaires may be used for quantifying HRQoL:

• EORTC QLQ-C30 − assesses generic HRQoL over the previous week.
• EORTC QLQ-MY20 − myeloma-specific assessment of HRQoL over the past week using a modified EORTC QLQ-C30 questionnaire.
• EQ-5D-5L − generic instrument for analyzing health status and global health that measures health on the day of the questionnaire.

Recent reports from the KarMMa and CARTITUDE-1 trials indicate that chimeric antigen receptor (CAR) T-cells show great promise at improving QoL. However, this claim contrasts with results frequently reported in clinical trials in which relapsed/refractory (R/R) patients with MM find that QoL is at best stabilized.¹

QoL changes with ide-cel

During the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, Nina Shah discussed the QoL changes reported in the KarMMA trial (NCT03361748) where the B-cell maturation antigen (BCMA)-directed CAR T-cell idecabtagene vicleucel (ide-cel) was used to treat patients with MM who were triple-class refractory.² This trial led to the approval of ide-cel as the first CAR T-cell therapy for MM.

This analysis used three methods for quantifying HRQoL:

• EORTC QLQ-C30 (n = 121)
• EORTC QLQ-MY20 (n = 120)
• EQ-5D-5L (n = 120)

The compliance rate was ≥ 80% for most visits.

QoL was assessed at screening, baseline (Day 1 of infusion), monthly during the first 6 months, and then every 3 months until 24 months or end of the study, and finally at disease progression or complete response (CR).

Results

Compared with the general population, patients on the KarMMa trial exhibited a lower level of functioning and increased symptom burden.

All functioning secondary subscales of the EORTC QLQ-C30 which measured role, social, and emotional functioning, showed clinically meaningful improvements during the trial. The improvements were statistically significant at multiple time points for the role and functioning subscales (Figure 1).

Figure 1. Patient responses at Day 1 and Month 9 assessed using EORTC QLQ-C30*

*Adapted from Shah et al.²

When focusing on gastrointestinal subscales using the EORTC QLQ-C30 instrument, clinical stability with a trend towards a decrease was observed with respect to constipation, nausea/vomiting, and diarrhea. Similar results were achieved for insomnia and dyspnea secondary subscales. A meaningful, and occasionally statistically significant, decrease in incidence was reached at multiple time points.

Using the EORTC QLQ-MY20 instrument stability or improvement was shown for the categories of Future Perspectives and Body Image at Month 9 compared with Day 1.

With the EQ-5D-5L index and EQ visual analogue scale (VAS), the scores for the patients in the KarMMa trial were lower than the general population at baseline. Between Day 1 and Month 9, clinically meaningful improvements were recorded using both HRQoL instruments (Figure 2).

Figure 2. Changes from baseline for patients in the KarMMa trial using 2 HRQoL instruments between Day 1 and Month 9*

D1, Day 1; M9, Month 9; VAS, visual analogue scale.
*Adapted from Shah et al.²

 In the triple-class exposed patients treated with ide-cel, clinically meaningful improvement in QoL were recorded.

QoL changes with cilta-cel

During the 7th World Congress on Controversies in Multiple Myeloma (COMy), an analysis of the impact of the anti-BCMA CAR T-cell ciltacabtagene autoleucel (cilta-cel) on HRQoL, was presented.³ These results were part of the phase Ib/II CARTITUDE-1 trial (NCT03548207) that included 68 patients with heavily pretreated (triple-class exposed) MM, where an overall response rate of 96.9% (95%  CI, 91.2–99.4) was achieved. Cilta-cel is undergoing accelerated assessment by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA).

HRQoL was assessed in the phase II portion of this trial using the following questionnaires:

• EORTC QLQ-C30, to assess the scales global health status (GHS), functional scales, and symptom scales.
• EORTC QLQ-MY20, to assess the scale emotional health status.
• EQ-5D-5L, to assess the scale current health status.

Of the 68 patients included in the study, the initial questionnaire completion rates at baseline were 92.6% for all the three questionnaires. At Day 100 this was ≥81.5% for all, and fell to 67.9% by Day 212 across the three questionnaires used.

Results

Physical Functioning and GHS increased over time up to Day 212, with median time to improvement of 1−2 months after infusion. Pain and Fatigue scores decreased over time in most groups with respect to the baseline, which showed a meaningful clinical improvement.

The same trend was seen at Day 100 postinfusion, as shown in Figure 3. With respect to the GHS, the greatest improvement was experienced by measurable residual disease (MRD)-negative patients who had reached CR/stringent CR. Patients who had no response/stable disease or a minimal response showed a decrease in GHS. A similar trend was seen for Physical Functioning.

Figure 3. Change in GHS and Physical Functioning at Day 100 postinfusion compared with baseline*

CR, complete response; GHS, global health status; MR, minimal response; MRD, measurable residual disease; NR, no response; PR, partial response; sCR, stringent CR; SD, stable disease; VGPR, very good PR.
*Adapted from Martin et al.^3
†One person with progressive disease was excluded due to lack of interviews.

Figure 4. Pain and Fatigue subscale scores at Day 100 postinfusion*

GHS, global health status; MR, minimal response; MRD, measurable residual disease; NR, no response; PR, partial response; sCR, stringent CR; SD, stable disease; VGPR, very good PR.
*Adapted from Martin et al.^3
†One person with progressive disease was excluded due to lack of interviews.

Conclusion

Both ide-cel and cilta-cel demonstrated improvements for HRQoL for patients with triple-class refractory MM. There was a trend toward greater improvements correlated with depth of response. It may be possible to derive further improvements in HRQoL over an extended period as responses may deepen over time; however, this requires further study.